The mesolimbic dopamine system, which consists of dopaminergic neurons in the ventral tegmental area (VTA) and their projections to the nucleus accumbens (NAc) and other forebrain regions, is an important neural substrate for the reinforcing and locomotor activating properties of several types of drugs of abuse, including opiates, cocaine and other stimulants, and ethanol. We have demonstrated a series of common, chronic biochemical actions of these drugs in the VTA and NAc, which could underlie part of the long-term changes in mesolimbic dopamine function that characterize drug addiction. These changes include an upregulation of tyrosine hydroxylase (the rate limiting enzyme in dopamine biosynthesis) in the VTA and an upregulation in the cAMP pathway in the NAc. Moreover, chronic administration of these drugs of abuse reduces levels of neurofilament proteins and increases levels of glial filament proteins specifically in the VTA, changes suggestive of neural insult or injury. These findings raise the possibility that neurotrophic factors, which exert a neuroprotective effect in many systems, may counter these and other actions of drugs of abuse. We have recently obtained direct support for this possibility. Infusion of certain neurotrophic factors directly into the VTA can prevent and reverse the ability of morphine and of cocaine to produce many of their typical biochemical actions in the mesolimbic dopamine system. One major objective of this Project is to further characterize such novel pharmacological actions of neurotrophic factors in this neural pathway. A second major objective of this Project is to investigate the related possibility that some of the previously identified biochemical changes that drugs of abuse produce in the mesolimbic dopamine system occur via drug regulation of neurotrophic factor signaling pathways in these brain regions. Support for this possibility comes from preliminary investigations wherein chronfc administration of morphine or cocaine has been shown to regulate levels of specific proteins involved in the neurotrophic factor signaling cascades, including ERK (also referred to as MAP kinase), phospholipase C-gamma-l, and JAK (a cytoplasmic protein tyrosine kinase). The proposed studies will further investigate drug regulation of these proteins, as well as their possible role in mediating morphine and cocaine regulation of some of the other biochemical adaptations identified in the VTA and NAc. For example, recent experiments in which levels of ERK1 were selectively reduced in the VTA by an antisense oligonucleotide strategy support the hypothesis that morphine regulation of ERK1 may mediate its upregulation of tyrosine hydroxylase in this brain region. Together, the proposed studies have the potential to reveal important new information concerning the molecular mechanisms of action of drugs of abuse on the mesolimbic dopamine system, which could contribute ultimately to the development of novel pharmacotherapies for addictive disorders.